Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001100.4(ACTA1):c.923A>G (p.Tyr308Cys)

CA10575963

224672 (ClinVar)

Gene: ACTA1 (HGNC:58)

Condition: alpha-actinopathy (MONDO:0100084)

Inheritance Mode: Autosomal dominant inheritance

UUID: 454fe219-c891-4f46-b624-4e5950727a16

Approved on: 2026-07-13

Published on: 2026-09-28

HGVS expressions

NM_001100.4:c.923A>G

NM_001100.4(ACTA1):c.923A>G (p.Tyr308Cys)

NC_000001.11:g.229431788T>C

CM000663.2:g.229431788T>C

NC_000001.10:g.229567535T>C

CM000663.1:g.229567535T>C

NC_000001.9:g.227634158T>C

NG_006672.1:g.7309A>G

ENST00000366683.4:c.923A>G

ENST00000684723.1:c.788A>G

ENST00000366683.3:c.554A>G

ENST00000366684.7:c.923A>G

NM_001100.3:c.923A>G

Likely Pathogenic

PP1_Moderate PP4 PP3 PP2 PM2_Supporting PS4_Supporting

BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS3 PS1 PM3 PM1 PM4 PM5 PM6 BA1 PVS1 BS4 BS3 BS1 BS2

Evidence Links 0

Expert Panel

Congenital Myopathies VCEP

Criteria Specification Information

Criteria Specification: ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Congenital Myopathies VCEP

The NM_001100.4(ACTA1):c.923A>G (p.Tyr308Cys) variant in ACTA1 is a missense variant predicted to cause a substitution of tyrosine by cysteine at amino acid 308. This variant is absent from gnomAD v4.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.898, which is above the threshold of ≥ 0.7, evidence that correlates with impact to ACTA1 function (PP3). ACTA1 has a low rate of benign missense variation and pathogenic missense variants are a common mechanism of disease in the autosomal dominant context as defined by the ClinGen Congenital Myopathies VCEP (PP2). This variant has been identified in the heterozygous state in an individual with a confirmed diagnosis of nemaline myopathy (PP4) (PMID: 32222963). This variant has also been identified in the heterozygous state in individuals with clinical features of myopathy or muscle dystrophy including an affected mother and two children (PP1_Moderate, PS4_Supporting) (PMID: 32222963, VCEP internal contributor). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant ACTA1-related alpha-actinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: PM2_Supporting, PP3, PP2, PP4, PP1_Moderate, and PS4_Supporting (VCEP Specifications Version 2.0).

PP1_Moderate

Internal information from the PathWest diagnostic laboratory in Western Australia has two families with the NM_001100.4(ACTA1):c.923A>G (p.Tyr308Cys) variant. In one family there is a single isolated case (proband from PMID: 32153140), in the other there are three affected individuals - a mother and two children. PP1 Moderate for 2 co-segregations for this family.

PP4

PMID: 32222963 reported a cohort of 48 patients with confirmed nemaline myopathy. Inclusion criteria included presenting with muscle weakness, delayed motor milestones, or exercise intolerance AND muscle biopsy showing presence of nemaline rods in muscle fibers after light and electron microscopy and lack of other specific pathological findings with other diseases such as immuno-metabolic myopathy, muscular dystrophy, and neurogenetic muscular disorders. An NGS panel of 700 genes identified this variant as HET in P39 who was a 19 year old male with congenital onset, parental testing not available, and no other proband-specific info available. For the presence of nemaline rods, PP4 at supporting level can be applied.

PP3

The REVEL score is 0.891, which is above the 0.7 threshold set by VCEP for damaging predictor

PP2

PP2 is applicable for autosomal dominant variants in ACTA1 per VCEP specifications

PM2_Supporting

This variant is absent from gnomAD v4.1.1

PS4_Supporting

One proband from PMID: 32222963 and a proband from the PathWest diagnostic laboratory in Western Australia (VCEP communication) meet PS4_Supporting criteria.

BP5

Not identified in a case with an alternate molecular basis for disease

BP7

Missense variant, criteria not applicable

BP2

Not observed with another ACTA1 variant

BP3

Missense variant, criteria not applicable

BP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BP1

BP1 not applicable to ACTA1 per VCEP specifications

PS2

Reported cases have not had familial segregation information

PS3

No functional studies performed for this variant presently

PS1

No previously reported variant resulting in the same amino acid change

PM3

Curating as AD variant, not observed with another ACTA1 variant

PM1

PM1 not applicable per VCEP specifications

PM4

Missense variant, criteria not applicable

PM5

PM5 not applicable: (ACTA1):c.922T>C (p.Tyr308His) VUS in ClinVar, unpublished, absent from gnomAD v4.1.1, damaging REVEL score (PM2_Supporting, PP3) variant currently at VUS

PM6

Reported cases have not had familial segregation information

BA1

Variant is absent from gnomAD v4.1.1

PVS1

Missense variant, criteria not applicable

BS4

Reported cases have not included familial segregation information

BS3

No functional studies performed for this variant presently

BS1

Variant is absent from gnomAD v4.1.1

BS2

Variant is absent from gnomAD v4.1.1

Curation History

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